The primary goal of this project is to understand the molecular and biochemical basis of the actions of histamine on cardiac tissue, in particular as they are related to activation of adenylate cyclase. Using a cell membrane fraction from guinea pig ventricle and a large number of both antagonists and agonists, we have demonstrated excellent correlations between affinities for the histamine-activated cyclase and for physiological H2 receptors. We have also found that a diverse group of compounds never before studied on H2 receptors appear to be competitive antagonists of the histamine-stimulated cyclase: D-LSD, amitriptyline, and calcium antagonists such as verapamil and diltiazem. Some of these compounds are more potent that the most active H2 antagonists suggesting that new types of H2 antagonists may be found among these structurally diverse classes of compounds.